1. Field of the Invention
The present disclosure generally relates to increasing left ventricular compliance. More particularly, the disclosure generally relates to systems and methods for cutting trabeculae carneae in order to increase left ventricular compliance.
2. Description of the Relevant Art
Left ventricular (LV) diastolic dysfunction (reduced compliance) was first identified in the 1970s as an important etiology producing shortness of breath in patients at rest and exertion, and as a major cause of hospital admission due to diastolic heart failure. Half of all heart failure admissions are due to left ventricular systolic failure (enlarged weak hearts), but half are caused by hearts with normal systolic function that are thickened with diastolic dysfunction. Despite 40 years developing solutions to improve left ventricular diastolic compliance, there have been no mediations or therapies invented which can acutely and permanently increase compliance. Medications which reduce calcium availability to the myocytes have not successfully improved diastolic compliance. As a result, medications are being used to slow the heart rate to prolong diastole (calcium and beta blockers), or decrease left ventricular filling pressures by moving down a fixed compliance curve with diuretics to reduce blood volume. However, there are no medications which can improve left ventricular diastolic compliance. That is because left ventricular compliance is known to be primarily related to the thickness of the left ventricular myocardium (normally 8-9 mm and increases to 12-16 mm) and the increase in the percentage of fibrosis which is known to occur as left ventricular hypertrophy develops (3% up to 12%). A genetic heart muscle condition called hypertrophic cardiomyopathy exists wherein a patient's heart can be as thick as 40 mm and the percentage of fibrosis can exceed more than 20% of the mass of the left ventricle.
The only therapeutic intervention currently available is the use of pharmacologicals to lower blood pressure in cases of left ventricular hypertrophy due to hypertension. However, although left ventricular hypertrophy can regress over months of time with normalization of blood pressure, left ventricular hypertrophy often cannot be completely normalized and often results in an increase in the percentage of fibrosis of the myocardium. Many other etiologies for left ventricular hypertrophy besides hypertension are recognized including diabetes, valvular heart disease, and hypertrophic cardiomyopathy. The relevant patient population is very large both in the U.S. (millions), and around the world.
While understanding of the human heart and the causes of diastolic dysfunction, from embryologic morphogenesis to normal and pathological function has advanced greatly over recent years, one feature, the trabeculae carneae, has received little attention. During embryologic morphogenesis of the heart, trabeculae carneae are some of the first features to arise in the developing cardiac tube (Bartram, Pediatr Cardiol 2007, 28:325-32). It is believed that the increased surface area afforded by these trabeculations facilitates diffusion, which is the primary means of nutrient acquisition by the developing cardiac tissue in lieu of a coronary system, which develops later in gestation (Bartram, Pediatr Cardiol 2007, 28:325-32). In parallel to the development of the coronary system, the trabeculae carneae undergo a process known as compaction, in which trabeculae carneae condense to form the myocardium (Bartram, Pediatr Cardiol 2007, 28:325-32). It has been proposed that the large intertrabecular spaces are transformed into capillaries during compaction (Gambetta, Pediatr Cardiol 2008, 29(2):434-7). Other structures of the heart are also thought to form from trabeculae carneae, such as the papillary muscles and chordae tendineae, as well as the inter-ventricular septum (Wenink, Br Heart J 1982, 48:462-8). In the human, not all trabeculae carneae are lost during development; trabeculations are still present in the apex and free-wall of the normal adult left ventricle (LV), and to a greater extent in the right ventricle (RV). The belief that these remaining trabeculae carneae are embryologic remnants (Wenink, Br Heart J 1982, 48:462-8) may explain why they have received little attention by the scientific community.
Although there has been little interest in the functional role of trabeculae carneae in the adult heart and their contribution to diastolic dysfunction, a few hypotheses have been proposed. One theory is that trabeculae carneae function to aid in systolic contraction by slowing incoming blood during diastole, thus reducing the kinetic energy that would otherwise have to be overcome during contraction (Burch, Am Heart J 1975, 89(2):261), (Burch, Angiology 1982, 33(4):221-7). Another theory is that the trabeculae carneae serve a nutritional role, directing blood flow to the papillary muscles and nodal conducting tissue within the heart (Taylor, Can J Cardiol 1999, 15(8):859-66). A final theory holds that trabeculae carneae serve the dual role of aiding in the force of systolic contraction through their own contractions and reducing residual blood volume at end-systole, as the intertrabecular spaces are reduced in size during contraction, forcing blood out of these spaces (Burch, Circulation 1952, 5:504-13). The scarcity of proposed functions of ventricular trabeculae carneae and the lack of empirical support for these theories evince that trabeculae carneae are poorly understood. Further, these proposed mechanisms are specious and are not consistent with a more recent understanding of the cardiovascular system.
Despite this lack of interest in trabecular function and their contribution to diastolic dysfunction, some attention has been paid to differences in trabeculae carneae between healthy hearts and several cardiovascular pathologies. The most drastic example is Left Ventricular Non-compaction (LVNC) or “Spongy Myocardium”, characterized by a layer of prominent trabeculae carneae and deep intertrabecular recesses which is at least twice as thick as the outer compacted layer of myocardium (Franqui-Rivera, P R Health Sci J 2008, 27(4):377-81). This disease is believed to be the result of an intrauterine arrest to the normal compaction of the trabeculae carneae during cardiac morphogenesis, although this model has been challenged due to the observation of “acquired LVNC” in adults with originally normal hearts (Franqui-Rivera, P R Health Sci J 2008, 27(4):377-81). Importantly, LVNC has been documented associated with cardiac abnormalities that promote high intracavitary ventricular pressures (Franqui-Rivera, P R Health Sci J 2008, 27(4):377-81). While this condition is extremely rare, several more common pathologies exist with such prominent ventricular trabeculations that they are often mistaken for LVNC (Franqui-Rivera, P R Health Sci J 2008, 27(4):377-81). Left ventricular hypertrabeculation (LVHT) is a distinct disorder from LVNC, and may occur in patients with neuromuscular disorders (Stollberger, Am J Cardiol 2002, 90:899-902). Dilated cardiomyopathy, acquired left ventricular hypertrophy secondary to systemic hypertension, and left-sided obstructive congenital cardiac malformations are also known to present with prominent trabeculae carneae (Bartram, Pediatr Cardiol 2007, 28:325-32). In addition to these pathologies where trabeculae careneae are enlarged, trabeculae carneae are also known to become fibrotic in heart-failure; the fibrotic content of trabeculae carneae has been found to be up to 2.1 fold greater in failing hearts as compared to non-failing hearts (Gruver, Basic Res Cardiol 1994, 89(2):139-48).
There have been more recent efforts to explain diastolic dysfunction on a molecular level. In the mammalian left ventricle, the diastolic pressure-volume relationship increases exponentially. This exponential relationship is believed to be an intrinsic property of cardiac tissue and has recently been attributed to the sarcomeric protein titin. Titin is the largest protein in the body, extending half the length of a sarcomere from the M-line to the Z-disc, where it functions as a bidirectional molecular spring which maintains the physiologic sarcomere slack length of ≈1.9 μm. Titin contains an extensible region which, in the absence of external force, maintains a folded conformation (Granzier, Circ Res 2004, 94:284-95). The extensible region is composed of three types of segments: the Ig segments, the PEVK segment, and the N2B segment. As the extensible region is stretched during diastole, these different segments extend at different sarcomere lengths, resulting in a unique passive force-extension relationship that generates mild resistance to stretch close to the slack length and greater resistance to stretch at further distances from the slack length (Granzier, Circ Res 2004, 94:284-95). In mammalian cardiac titan, the N2B segment is found in two isoforms denoted N2B and N2BA. The N2BA isoform contains the N2B segment, but also an additional N2A segment, which results in additional extensibility of the titin molecule consistent with a more compliant LV during diastolic filling. Therefore cardiac myocytes that express high levels of N2B titin have higher passive stiffness than myocytes that express N2BA titin (Granzier, Circ Res 2004, 94:284-95). Mammalian species express one or both cardiac titin isoforms, and the relative amounts of each isoform vary greatly between species. Importantly, the ratio of titin isoforms is not fixed, and undergoes changes in response to chronic mechanical loading of the heart (Granzier, Circ Res 2004, 94:284-95). For instance, titin isoform switching is likely a contributor to diastolic dysfunction, as van Heerebeek et al. found that the titin N2BA/N2B ratio was lower in the myocardium of patients with diastolic heart failure (17/83) than in patients with systolic heart failure (35/65) (Van Heerebeek, Circulation 2006, 113:1966-73).
Despite the large role that titin is believed to play in determining passive myocardial stiffness, it is only part of the picture. Other factors such as myocyte hypertrophy, and the amount of collagen, the abundance of collagen type 1, and collagen cross-linking in the extracellular matrix also likely contribute to the increased myocardial stiffness characteristic of diastolic dysfunction (Borlaug, Eur Heart J 2011, 32:670-9).
Therefore a system and/or method which results in increase in left ventricular compliance is highly beneficial.